Ablating Adenovirus Type 5 Fiber–CAR Binding and HI Loop Insertion of the SIGYPLP Peptide Generate an Endothelial Cell-Selective Adenovirus

Nicklin, Stuart A.; Seggern, Dan J. Von; Work, Lorraine M.; Pek, Don C.K.; Dominiczak, Anna F.; Nemerow, Glen R.; Baker, Andrew H.

doi:10.1006/mthe.2001.0489

Cited by 130 publications

(94 citation statements)

References 40 publications

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“…Although a phage display library has been used to identify targeting peptide motifs, the incorporation of the peptides selected by phage display into the adenoviral capsid has not been successful in developing targeted vectors except for a few cases, [11][12][13] possibly due to the peptide-induced conformational change of the virus capsid and the loss of specificity and affinity of ligandreceptor binding. 14 We have recently developed a novel system for producing adenoviral libraries displaying a variety of peptides on the HI-loop of the fiber knob and established a procedure to select an adenoviral vector with high infectivity in target cells.…”

Section: Introductionmentioning

confidence: 99%

Oncolytic virus therapy for pancreatic cancer using the adenovirus library displaying random peptides on the fiber knob

Nishimoto

Yoshida²,

Miura³

et al. 2009

Gene Ther

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A conditionally replicative adenovirus is a novel anticancer agent designed to replicate selectively in tumor cells. However, a leak of the virus into systemic circulation from the tumors often causes ectopic infection of various organs. Therefore, suppression of naive viral tropism and addition of tumor-targeting potential are necessary to secure patient safety and increase the therapeutic effect of an oncolytic adenovirus in the clinical setting. We have recently developed a direct selection method of targeted vector from a random peptide library displayed on an adenoviral fiber knob to overcome the limitation that many cell type-specific ligands for targeted adenovirus vectors are not known. Here we examined whether the addition of a tumor-targeting ligand to a replication-competent adenovirus ablated for naive tropism enhances its therapeutic index. First, a peptide-display adenovirus library was screened on a pancreatic cancer cell line (AsPC-1), and particular peptide sequences were selected. The replication-competent adenovirus displaying the selected ligand (AdDCAR-SYE) showed higher oncolytic potency in several other pancreatic caner cell lines as well as AsPC-1 compared with the untargeted adenovirus (AdDCAR). An intratumoral injection of AdDCAR-SYE significantly suppressed the growth of AsPC-1 subcutaneous tumors, and an analysis of adenovirus titer in the tumors revealed an effective replication of the virus in the tumors. Ectopic liver gene transduction following the intratumoral injection of AdDCAR-SYE was not increased compared with the AdDCAR. The results showed that a tumor-targeting strategy using an adenovirus library is promising for optimizing the safety and efficacy of oncolytic adenovirus therapy.

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Section: Introductionmentioning

confidence: 99%

Oncolytic virus therapy for pancreatic cancer using the adenovirus library displaying random peptides on the fiber knob

Nishimoto

Yoshida²,

Miura³

et al. 2009

Gene Ther

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“…6 Infectious and particle titers were determined for each preparation of virus used as described. 26,27 Cells were plated into 96-well plates at 3 Â 10 4 cells/well 24 h prior to infection. Cells were then incubated with virus for 10 min, 30 min or overnight.…”

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confidence: 99%

Dual targeting of gene delivery by genetic modification of adenovirus serotype 5 fibers and cell-selective transcriptional control

et al. 2004

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Adenovirus (Ad)-mediated gene delivery is a promising approach for genetic manipulation of the vasculature and is being used in both preclinical models and clinical trials. However, safety concerns relating to infection of nontarget tissue and the poor infectivity of vascular cells compared to other cell types necessitates Ad vector refinement. Here, we combine a transductional targeting approach to improve vascular cell infectivity through RGD peptide insertion into adenovirus fibers, combined with transcriptional targeting to endothelial cells using a E1 kb fragment of the fms-like tyrosine kinase receptor-1 (FLT-1) promoter. Single-and double-modified vectors were characterized in human cell lines that either support or have silenced FLT-1 expression.In rat hepatocytes and endothelial cells, the double modification substantially shifted transduction profiles toward vascular endothelial cells. Furthermore, in intact aortae derived from spontaneously hypertensive rats that display enhanced av integrin expression on dysfunctional endothelium, enhanced levels of transduction were observed using the double-modified vector but not in aortae derived from normotensive control rats. Our data indicate that Admediated transduction can be beneficially modified in vitro and in vivo by combining fiber modification and a cellselective promoter within a single-component vector system.

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“…75,78,79 Alternatively, small ligands such as FLAG, RGD, polylysine and transferrin receptor binding peptides can be incorporated into the highly flexible HI loop of fiber. [31][32][33][34] Belousova and co-workers 37 have recently demonstrated the capacity of the HI loop to accommodate large (480 aa) targeting ligands by successfully generating infectious virions containing fragments of the penton base RGD loop inserted into the HI loop. Their data clearly show that the inserted fragments were capable of mediating a novel CAR-independent, integrin-dependent entry pathway; however, the ligand chosen was relatively nonstructured and as such did not address the issue of possible ligand-fiber structural incompatibilities.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the utility of the HI loop as a site of ligand insertion has been successfully demonstrated for a number of small peptide targeting ligands, or larger, unstructured ligands. [31][32][33][34][35][36][37] To overcome suboptimal expression of CAR in cancer cells and to demonstrate the utility of the HI loop to accommodate relatively large targeting ligands, we sought to expand the viral tropism by insertion of the epidermal growth factor (EGF)-like domain of heregulin-a (HRG) into the HI loop. HRGa, also called neuregulin and Neu differentiation factor, 38,39 binds directly via the EGF-like domain [40][41][42] to HER3/ErbB3 and/or HER4/ErbB4, members of the EGF receptor family, which then homodimerize or heterodimerize with HER2/ErbB2 to initiate a transmembrane signal.…”

Section: Introductionmentioning

confidence: 99%

HER3 targeting of adenovirus by fiber modification increases infection of breast cancer cells in vitro, but not following intratumoral injection in mice

et al. 2012

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Despite the tremendous potential of adenovirus (Ad) as a delivery vector for cancer gene therapy, its use in clinical settings has been limited, mainly as a result of the limited infectivity in many tumors and the wide tissue tropism associated with Ad. To modify the tropism of the virus, we have inserted the epidermal growth factor-like domain of the human heregulin-a (HRG) into the HI loop of Ad5 fiber. This insertion had no adverse effect on fiber trimerization nor did it affect incorporation of the modified fiber into infectious viral particles. Virions bearing modified fiber displayed growth characteristics and viral yields indistinguishable from those of wild-type (wt) virus. Most importantly, HRG-tagged virions showed enhanced infection of cells expressing the cognate receptors HER3/ErbB3 and HER4/ErbB4. This was significantly reduced in the presence of soluble HRG. Furthermore, HER3-expressing Chinese hamster ovary (CHO) cells were transduced by the HRG-modified virus, but not by wt virus. In contrast, CHO cells expressing the coxsackie-Ad receptor were transduced with both viruses. However, infection of an in vivo breast cancer xenograft model after intratumoral injection was similar with both viruses, suggesting that the tumor microenvironment and/or the route of delivery have important roles in infection of target cells with fiber-modified Ads.Cancer Gene Therapy (2012) 2,3 In addition to being among the most extensively studied viral vectors, Ads can be easily and economically manipulated, maintained and propagated to produce high titer stocks. 4,5 Moreover, they have the capacity to carry relatively large fragments of exogenous DNA into a wide range of cell and tissue types. 4,5 Subgroup C Ads (exemplified by the most widely used Ad5 and Ad2) attach to and enter host cells in a two-step process. 6 The initial recognition/attachment step is mediated by interactions between the knob component of fiber protein on the Ad capsid and the extracellular domain of the coxsackieadenovirus receptor (CAR) on the host cell surface. 7-11 This attachment is followed by a second interaction between the RGD motif in the penton base of the virus capsid and a v b 3 or a v b 5 cell surface integrins (secondary Ad receptors), which allows viral entry via receptor-mediated endocytosis. [12][13][14][15] Both the primary and secondary Ad receptors are expressed on a wide range of tissues leading to the observed broad tissue tropism of Ads. 16,17 Unfortunately, a large number of tumor cells appear relatively refractory to Ad infection because of limited surface expression of the primary Ad receptor. 1,[18][19][20][21][22][23] This observation has been a driving force behind recent intensive efforts to generate Ad viral vectors with altered tropism.

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Ablating Adenovirus Type 5 Fiber–CAR Binding and HI Loop Insertion of the SIGYPLP Peptide Generate an Endothelial Cell-Selective Adenovirus

Cited by 130 publications

References 40 publications

Oncolytic virus therapy for pancreatic cancer using the adenovirus library displaying random peptides on the fiber knob

Oncolytic virus therapy for pancreatic cancer using the adenovirus library displaying random peptides on the fiber knob

Dual targeting of gene delivery by genetic modification of adenovirus serotype 5 fibers and cell-selective transcriptional control

HER3 targeting of adenovirus by fiber modification increases infection of breast cancer cells in vitro, but not following intratumoral injection in mice

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